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10.1245/s10434-006-9272-9
Annals of Surgical Oncology 14:1612-1617 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Intraoperative Evaluation of Sentinel Lymph Nodes for Metastatic Melanoma by Imprint Cytology

Victoria Soo, BS1, Perry Shen, MD1, Rita Pichardo, MD2,3, Hossam Azzazy, MD2, John H. Stewart, MD1, Kim R. Geisinger, MD2 and Edward A. Levine, MD1

1 Surgical Oncology Service and Department of Surgery, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157
2 Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
3 Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Correspondence: Address correspondence and reprint requests to: Edward A. Levine, MD; E-mail: elevine{at}wfubmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Sentinel lymph node biopsy (SLN) has revolutionized nodal staging. Accurate intraoperative evaluation of SLN permits a single procedure, with lymphadenectomy being performed during the initial operative procedure when the SLN is positive. There is a paucity of literature on intraoperative imprint cytology (IIC) evaluation of the SLN in melanoma. The purpose of this article is to present an update to our experience with IIC for SLN in melanoma.

Methods: Melanoma patients had SLNs examined by IIC. SLNs were bisected, and imprints were made from each half. Imprints were stained with hematoxylin and eosin and with Diff-Quik. Paraffin-embedded sections were examined with multiple hematoxylin and eosin–stained sections from the SLNs in conjunction with immunohistochemical staining for S-100, Melan-A, and HMB-45 proteins.

Results: Metastases were identified in 40 (17%) of 229 patients. Of these, 13 patients were detected by IIC (sensitivity, 33%). The negative predictive value was 88%. No false-positive results were identified (specificity, 100%). The positive predictive value was 100%. The accuracy of IIC was 78%. The sensitivity for detecting macrometastases (>2 mm) was better than that for detecting micrometastases (≤2 mm): 62% vs. 16% (P < .01). Patients with positive SLNs by IIC had lymphadenectomy under the same anesthetic. A total of 533 nonsentinel lymph nodes were identified in 42 patients. Only two patients (8%) had positive nonsentinel lymph nodes after a negative IIC.

Conclusions: IIC is a viable alternative to frozen sectioning when intraoperative evaluation is desired. IIC is significantly more sensitive for macrometastases. IIC evaluation of SLNs in melanoma makes a single operative procedure possible for a significant proportion of patients with regional nodal metastases.

Key Words: Melanoma • Metastatic • Surgery • Sentinel lymph node • Cytopathology • Imprint


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The incidence of melanoma has been increasing rapidly in recent decades.1,2 The most important prognostic factor for survival of melanoma patients is tumor involvement of regional lymph nodes.1–3 Traditionally, elective lymphadenectomy has been considered a treatment option for patients at high risk for metastasis. However, this procedure is only potentially beneficial to patients with nodal disease, and it confers significant morbidity, with a complication rate ranging from 25% to 61% after dissection.4,5 Complete lymphadenectomy is associated with the risk of lymphedema, wound complications, limb dysfunction, and, rarely, secondary malignancy.4,5 The introduction of sentinel lymph node (SLN) mapping has allowed identification of the subset of patients with clinically occult metastatic disease who may benefit from complete regional lymphadenectomy.1,2,6 SLN biopsy is now considered a standard method of surgical staging in cutaneous melanoma. Patients who are found on permanent pathologic evaluation to have a positive SLN typically return to the operating room for a completion lymphadenectomy. Various authors have advocated the intraoperative evaluation of the SLN at the time of biopsy.7,8 This allows for a one-step surgical procedure for both mapping and lymph node dissection should the SLN contain metastatic melanoma. Intraoperative pathologic evaluation of the SLN is most commonly performed by using intraoperative frozen sections.1,8 An alternate method is intraoperative imprint cytology (IIC), which involves analysis of imprints of a cut surface of a lymph node. We have previously shown that IIC is as sensitive and specific as frozen-section analysis.8 Compared with frozen-section analysis, IIC analysis is less expensive and faster, and there is no tissue loss, which is attendant to frozen sections with cryostat processing. In this study, we updated our results by using IIC investigation of SLNs in a consecutive series of 234 patients with melanoma.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Data Collection
Between December 1998 and September 2005, 234 consecutive patients with clinically localized cutaneous melanoma underwent SLN mapping and biopsy with IIC analysis. The average age of male patients was 53 years, and the average age of female patients was 52 years. Primary melanomas were located on the trunk in 55 patients, lower extremity in 44 patients, upper extremity in 65 patients, and head and neck in 70 patients. Of the 234 patients with melanoma, the American Joint Committee on Cancer primary tumor (T) classification was 25 T1 and under, 93 T2, 67 T3, and 49 T4 primary melanomas. This retrospective analysis was approved by our institutional review board.

Surgical Protocol
A standard protocol was used to identify the SLN. The dermis around the biopsy site was injected with filtered technetium sulfur colloid (.5–1.0 mCi) before surgery. A lymphoscintigram was obtained in the nuclear medicine department before the patients arrived in the operative suite. A gamma probe (Neoprobe 2000) was used during surgery to detect the SLN. In addition, in all cases, perilesional intradermal injections of isosulfan blue provided visual identification of the SLN. After injection of isosulfan blue, the site was massaged for 5 minutes before an incision was made. The SLNs were then harvested and sent fresh to pathology for intraoperative and permanent-section evaluation. Lymph nodes were considered SLNs if they were blue and/or concentrated tracer (99mTc). SLNs were harvested until no node in the basin had counts >10% of the hottest SLN. The SLN was obtained at the initial phase of the operative procedure, and excision of the primary lesion was generally performed as the IIC was evaluated. This minimized the effect of IIC on total operative time.

Pathologic Examination
In all cases, excised lymph nodes submitted for IIC were bisected along the long axis. Care was taken to obtain complete cross sections of the maximum diameter, preferably including the hilum and the marginal sinus. For each lymph node half, a pair of imprints was made by gently touching the cut surface of the SLN to a glass slide. One set of imprints from each pair was air-dried and stained with the Diff-Quik stain. The second set from each surface was immediately fixed in 95% ethanol for 3 minutes and then stained with hematoxylin and eosin (H&E). The imprints were then immediately examined by a pathologist. A diagnosis of either positive or negative for tumor was rendered, and the surgical team was notified of the result. The SLN was then fixed in 10% formalin, processed in the usual manner, and paraffin-embedded. An initial H&E section of each half of the SLN was cut from the paraffin block. If initial review of the H&E-stained sections was negative, a melanoma protocol consisting of an additional three H&E stained levels cut at 50-µm intervals in conjunction with immunohistochemical stains for S-100, Melan-A, and HMB-45 on the first of the three levels was performed (Fig. 1Go). Immunohistochemical studies were performed by using the avidin-biotin-peroxidase complex method.9 Primary antibodies included S-100 (rabbit anti-cow S-100; DAKO, Carpinteria, CA), HMB-45 (monoclonal mouse anti-human melanoma; DAKO), and Melan-A (monoclonal mouse anti-human Melan-A, clone A103; DakoCy-tomation, Carpinteria, CA). Immunohistochemical stains were considered positive for metastatic melanoma if there was strong immunoreactivity in cell clusters or individual cells that demonstrated anatomical and cytological features of metastatic tumor cells.


Figure 1
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  		FIG. 1. A microscopic focus of metastatic melanoma is present in the subcapsular sinus of a sentinel lymph node. The intraoperative touch imprint was negative (stain, hematoxylin and eosin; original magnification, x 100).

 
When discrepancies existed between the intraoperative and permanent-section results, slides were reviewed by an independent pathologist in an attempt to determine the cause of the discrepancy. When non-SLNs were obtained, they were examined by using standard pathologic techniques. If >4 mm in width, non-SLNs were sectioned; if <4 mm, non-SLNs were submitted whole. Routinely, a single H&E-stained section of the non-SLNs was examined, but in several cases multiple levels were obtained in an attempt to verify the presence of metastases. For the purposes of this study, we defined nodal micrometastasis as ≤2 mm and macrometastasis as >2 mm, as measured directly on the slide.10 Statistical significance was defined as a P < .05 and was determined by {chi}2 and Fisher’s exact tests, as appropriate.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
SLNs were found in 229 (98%) of 234 patients. The average age was 56 years (range, 11–87 years). A total of 655 SLNs were excised (mean, 2.9 per patient; range, 1–13 per patient). Metastatic melanoma was identified in 40 patients (17%) on permanent-section evaluation of the SLN. In only 13 of these patients were metastases detected by IIC (sensitivity, 33%). On a per-patient basis, the negative predictive value was 88%, positive predictive value was 100%, and overall accuracy was 78%. The relationship between classification of tumor and sensitivity is presented in Table 1Go.10 The SLN was obtained as the initial phase of the operative procedure, with excision of the primary lesion generally being performed as the IIC was evaluated. This minimized the effect of IIC on total operative times. The average turnaround time of IIC was approximately 25 minutes.


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  		TABLE 1. Comparison of intraoperative imprint cytological evaluation relative to permanent-section evaluation by tumor size classification
 
On a per–lymph node basis, 655 SLNs were identified. Only 49 (7%) harbored metastatic melanoma on permanent-section evaluation. Of these 49 positive nodes, only 22 were detected by IIC (sensitivity, 45%). The negative predictive value was 96%. Of the 27 false-negative lymph nodes by IIC, 18 were discovered on initial H&E–stained permanent sections, 7 were discovered in deeper H&E–stained levels, and 2 were identified only on HMB-45, Melan-A, and S-100 immunohistochemically stained sections. One lymph node was detected by immunohistochemical staining, which incorrectly identified a subcapsular nevus as a metastasis, although it was known to be a nevus at the initial pathologic evaluation. However, because the IIC in this case was negative, the specificity was 100%, with a positive predictive value of 96 % and an overall accuracy of 95%.

The sensitivity of detecting metastatic disease in SLN by imprint cytology was significantly higher for macrometastatic disease (metastases >.2 cm) than for micrometastatic disease (metastases ≤.2 cm; P < .01; Table 2Go).10 A total of 533 non-SLNs were identified in 42 patients who underwent node dissection. Sixteen non-SLNs from four patients harbored metastatic melanoma. All four patients with positive non-SLNs had stage T3 nodular melanomas. Two of these patients had positive SLNs not detected by imprint cytology. Of these patients, one had known macrometastases to the SLN, and 19 of 20 were non-SLN positive. The second patient had micrometastases to the SLN and one non-SLN positive for metastatic disease.


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  		TABLE 2. Sensitivity of intraoperative imprint cytology: relative size of metastases
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Accurate intraoperative evaluation of SLNs permits a one-step dissection of the regional lymph node basin during the initial operative procedure if metastases are found. For intraoperative analysis, frozen sectioning and cytological methods, with or without the use of intraoperative immunohistochemical stains for HMB-45, Melan-A, and S-100, have been used to evaluate the SLN for metastatic melanoma.1,8 These methods have had variable reported sensitivities, ranging from 33% to 59%, a factor that ultimately is affected by the method by which the SLN is evaluated. Sensitivity is an important factor because intraoperative evaluation must detect a high enough proportion of positive cases to justify the expense and time of such an approach. Because most patients will ultimately be node negative, high specificity may be more critical; the goal of the SLN biopsy is to stage the disease precisely so that regional lymph node dissection may be avoided when the SLN is negative. Even modest false-positive rates would result in an unacceptable number of unnecessary regional lymph node dissections.

Frozen-section examination has been the most popular method of evaluating the SLN during surgery for metastatic melanoma. The results of these studies were comparable to similar frozen-section studies for breast carcinoma.11–28 Several studies have evaluated the use of cytological methods to evaluate primary and metastatic melanoma,29 whereas only a handful of studies exist that detail experience with IIC evaluation of the SLN for melanoma.1,8,34,35 The cost-effectiveness of each technique is also an important consideration. At our institution (as of October 2004), the cost evaluating two SLNs was $51 via IIC versus $146 by frozen section.

In this study, the sensitivity of IIC was 33%, and the specificity was 100%. These results are similar to those reported from our previous study of 93 patients.8 Overall, 17% of cases were found to have nodal metastases. This can partially be attributed to the number of patients with T1 lesions in our study, of which none had metastases to the SLN (n = 25). We no longer perform SLN biopsy in such patients.

The rate of nodal positivity and IIC sensitivity increased with increasing tumor thickness. The sensitivity of intraoperative analysis for the detection of metastatic melanoma was similar in patients with T2, T3, and T4 lesions, ranging from 21% to 47% (Table 1Go). A problematic area is the poor sensitivity of detecting micrometastatic disease compared with macrometastatic disease during surgery. There was a significant disparity between detection of micrometastatic disease versus macrometastatic disease in this study (Table 2Go). Although additional sections of harvested SLNs and/or intraoperative immunohistochemistry could improve this, it would significantly increase the cost and time requisite of intraoperative analysis.

Imprint cytology is a much more practical method of evaluating lymph nodes during surgery, and it seems to be a viable alternative to frozen sectioning. Metastatic melanoma, when present on IIC, can usually be easily identified, especially when metastases are large (Fig. 1Go). Melanoma cells are usually much larger than native lymphocytes. Binucleation, intracytoplasmic melanin pigment, and nuclear pseudoinclusions are also distinguishing features. Metastatic melanoma usually has a distinct single dispersed cell pattern, although cellular aggregates may be observed. Occasionally, lymph node histiocytes may contain both hemosiderin and melanin pigments, thus making interpretation difficult. However, histiocytes, in contrast to melanoma cells, have lower nuclear to cytoplasmic ratios, round or oval regular nuclei, and inconspicuous nucleoli and should not be difficult to distinguish from the usually much more atypical metastatic melanoma cells.

Several factors influence the sensitivity of both imprint cytology and frozen-section evaluation of SLN. The first critical factor is the size of the metastasis. In this study, detection of macrometastases usually occurred after examination of the first level. Detection of micrometastases was more problematic because they were unpredictably scattered throughout the lymph node. In this study, regardless of the size of the SLN, lymph nodes were bisected only before IIC. Examination of the lymph node at thin 2- to 3-mm sections rather than bisecting the node increases the sensitivity of detecting breast carcinoma by IIC and, likely, would increase the sensitivity of detecting melanoma as well.36

The method of permanent-section evaluation of the lymph node is a critical factor in defining the sensitivity of IIC. In evaluating SLNs for breast carcinoma, when multiple permanent H&E step sections with cytokeratin immunohistochemistry are used to evaluate permanent sections, a higher percentage of micrometastases are detected than when the lymph node is examined less rigorously.36 Alternatively, when lymph nodes are not examined in such a rigorous manner, micrometastases are frequently missed, a factor that can artificially inflate the sensitivity of intraoperative evaluation. Unfortunately, with metastatic melanoma, metastases can be very small and are sometimes detectable only with step sectioning and/or immunohistochemical stains (Fig. 1Go). This results in increased false-negative rates for intraoperative evaluation. Indeed, in our study, there were two patients with single-cell metastases that were detected only by immunohistochemical staining.

In addition, benign capsular nevus cell rests can be a potential diagnostic pitfall. We have previously shown that nodal nevi are more prevalent in SLNs in patients with melanoma-associated cutaneous nevi.37 This is likely due to mechanical transport of nevus cells through lymphatics.37,38 The cytological features of benign capsular nevus cells and their location within the capsule, rather than the subcapsular sinus, should alert the pathologist to the benign nature of these cells by histology. In our study, one lymph node incorrectly identified metastatic melanoma by immunohistochemical staining was a benign subcapsular nevus.

The size of the lymph node is a factor that can affect intraoperative evaluation of the SLN. This problem usually affects only frozen-section evaluation of the SLN because it can be difficult to cut and transfer onto a glass slide large pieces of lymph node, especially when partially or wholly replaced by fat. There are no such limitations with IIC. If the lymph node is too large, then multiple imprints of the cut surface can be pieced together quite easily to survey the entire cut surface.

The chance of detecting SLN metastases in melanoma is approximately 17% in this series; this is consistent with our previous study and with recent literature.8,39,40 Because the sensitivity of imprint cytology is 33%, then metastases are detected in approximately 6% of melanoma patients during surgery. Because most patients will not require complete nodal dissections, a significant delay in completion of the operative procedure for IIC would significantly decrease any benefit accrued from IIC. However, because dissection of the SLN is the initial phase of the operative procedure and excision of the primary site proceeds while the pathologist evaluates the node with IIC, the delay requisite to this approach is minimized. Further, the benefit of finding a positive SLN and performing the completion lymphadenectomy under the same anesthetic represents a significant advantage to the subset of patients found to have a positive IIC. Specifically, avoidance of a second trip to the operative suites, with its substantial attendant costs, as well as a decreased number of office visits (to schedule the completion lymphadenectomy), make IIC advantageous to such patients. Such a cost-benefit analysis is beyond the scope of this article but warrants further study.

Any potential benefit of intraoperative analysis of SLN for melanoma rests on the thesis that completion of the lymphadenectomy in the setting of a positive nodal metastasis is routinely warranted. Although this is the currently accepted practice, whether a completion lymphadenectomy is mandatory after a positive sentinel node is found has recently been challenged.2 Our experience and that of others suggests2 that most patients (>90% in this series) have all nodal metastases removed with sentinel node biopsy procedures. Only 8% of patients with a negative IIC and positive permanent sections had additional nodal metastases found in non-SLNs in lymphadenectomy specimens. This certainly supports the thesis of the multicenter selective lymphadenectomy trial (MSLT-2), which is currently evaluating whether completion of the nodal dissection when positive SLNs are encountered is effective. However, we continue to suggest complete lymphadenectomy when nodal metastasis is encountered unless the patient is part of a clinical trial.

Our experience suggests that intraoperative evaluation of the SLN for metastatic melanoma mandates flexibility in operative scheduling, which may not be practical for some institutions. We have not found such flexibility to be a problem at our institution. Further, even with a negative IIC, the risk of returning to the operative suites for completion lymphadenectomy remains approximately 10%, and patients should be made aware of this during pre-operative consultations.

Imprint cytology is as sensitive and specific as frozen-section examination of the SLN, and IIC has several advantages over frozen-section evaluation for melanoma. Imprint cytology is less expensive and faster than frozen sectioning and does not waste tissue in the cryostat. With frozen section, theoretically, a small micrometastasis could be cut o3 the tissue block and fall to the bottom of the cryostat, never to be discovered. Furthermore, with IIC the pathologist does not have to attempt to cut lymph nodes that may be largely replaced by fat, and freezing artifact is not introduced into the tissue when imprints are made. However, for those institutions that are facile with this method, IIC is the preferred method of in-traoperative evaluation of SLNs for melanoma.

Received for publication March 22, 2006. Accepted for publication October 4, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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